Project Summary The pollution of polycyclic aromatic hydrocarbons has become a threat in environmental health because of their toxicities to a variety of organisms including humans. Previous epidemiological studies demonstrated a close relationship between PAH exposures and many acute and chronic human diseases. Evidence in the toxicity changes of PAHs under effects of environmental stressors in the past few years raised a bigger concern in the risk of modified PAHs considering the fast-changing environment conditions led by climate change. However, very limited efforts have been made to understand the effects of environmental changes on PAH toxicities to human health. The long-term goal of our study is to understand the molecular mechanism of human inflammatory skin diseases caused by the PAH compounds, and how environmental factors affect the dermatoxicities of these compounds. The central hypothesis of the proposed study is that environmental impacts on structures of PAH compounds will change their toxicities to human skin. Three specific aims will have to be accomplished to complete the test of the hypothesis. The three specific aims include, 1) to identify the photodegradation of aqueous PAHs under the effects of water salinity and acidified water condition initiated by increased atmospheric CO2 level; 2) to discover the dermatoxic pathway of PAHs to human keratinocytes under the environmental impact; and 3) to verify the environment-modified PAH dermatoxic pathway in vivo. To address these specific aims, a standardized PAH protocol will be established in this study. Selected PAH compounds will be degraded under photo exposure within different surrounding salinity and pCO2 levels. These environmental factors are expected to interact with the photodegradation of these chemicals. The toxicities of the PAH chemicals with photo-modification at different salinity and pCO2 levels will be evaluated using three-dimensional human keratinocyte culture and keratinocyte/fibroblast co- culture models. A putative PAH pathogenic pathway in keratinocytes will be validated using the 3D keratinocytes constructs combined with gene functional analyses with siRNA or gene overexpression assays. The relationship between the identified pathway and the skin inflammatory responses will be investigated using a mouse skin inflammation model. As a study in predictive toxicology, the approach of this study takes advantage of the basic knowledge of biological pathways to develop in vitro and animal-based tests to predict adverse effects of chemical exposure, which is a priority component of the Environmental Health Sciences.